Orosomucoid 2 maintains hepatic lipid homeostasis through suppression of de novo lipogenesis

Non-alcoholic fatty liver disease (NAFLD) is caused by imbalance in lipid metabolism. In this study, we show that the hepatokine Orosomucoid 2 (ORM2) is a key regulator of de novo lipogenesis in the liver. Hepatic and plasma ORM2 levels are markedly decreased in obese murine models and NAFLD patients. Through multiple loss- and gain-of function studies, we demonstrate that ORM2 is essential to maintain hepatic and systemic lipid homeostasis. At the mechanistic level, ORM2 binds to inositol 1, 4, 5-trisphosphate receptor type 2 (ITPR2) to activate AMP-activated protein kinase (AMPK) signaling, thereby inhibiting sterol regulatory element binding protein 1c (SREBP-1c)-mediated lipogenic gene program. Notably, intraperitoneal injections of recombinant ORM2 protein or stabilized ORM2-FC fusion protein markedly improved liver steatosis, steatohepatitis and atherosclerosis in preclinical mouse models, without adverse effects on body weight or food intake. Thus, these findings suggest that ORM2 may serve as a potential target for therapeutic intervention in NAFLD, NASH and related lipid disorders. Male ob/ob mice were purchased from GemPharmatech Company (Nanjing, China). Mice were randomly divided into two groups and administered with adenovirus containing GFP or ORM2 (1×10E9 plaque-forming units/mouse) through tail vein injection, respectively. 12 days later, mice were sacrificed and liver tissues were harvested for RNA-Seq analysis and other experiments. The objective of RNA-Seq is to identify potential target genes of ORM2 in improving liver steatosis. In our datasets, Ad-GFP means ob/ob mice transduced with adenovirus containing GFP. Ad-ORM2 means ob/ob mice transduced with adenovirus containing ORM2. n=4 in each group.

非酒精性脂肪性肝病（Non-alcoholic fatty liver disease, NAFLD）由脂质代谢失衡（lipid metabolism imbalance）引发。本研究证实，肝源性因子类黏蛋白2（Orosomucoid 2, ORM2）是肝脏从头脂肪生成（de novo lipogenesis）的关键调控因子。肥胖小鼠模型与NAFLD患者的肝脏及血浆ORM2水平均显著降低。通过多组功能缺失与功能获得性实验，我们证明ORM2对维持肝脏及全身脂质稳态至关重要。在分子机制层面，ORM2可结合1,4,5-三磷酸肌醇受体2型（inositol 1,4,5-trisphosphate receptor type 2, ITPR2）以激活腺苷酸活化蛋白激酶（AMP-activated protein kinase, AMPK）信号通路，从而抑制固醇调节元件结合蛋白1c（sterol regulatory element binding protein 1c, SREBP-1c）介导的脂肪生成基因程序。值得注意的是，腹腔注射重组ORM2蛋白或稳定型ORM2-FC融合蛋白，可显著改善临床前小鼠模型的肝脏脂肪变性、脂肪性肝炎与动脉粥样硬化，且对小鼠体重或摄食量无不良影响。综上，本研究结果提示ORM2可作为NAFLD、非酒精性脂肪性肝炎（NASH）及相关脂质紊乱的潜在治疗干预靶点。雄性ob/ob小鼠购自GemPharmatech公司（中国南京）。将小鼠随机分为两组，分别通过尾静脉注射携带绿色荧光蛋白（Green Fluorescent Protein, GFP）或ORM2的腺病毒（1×10^9噬斑形成单位/每只小鼠）。12天后处死小鼠，采集肝脏组织用于RNA测序（RNA-Seq）分析及其他实验。本RNA-Seq实验的目的是筛选ORM2改善肝脏脂肪变性的潜在靶基因。本数据集中共包含两组样本：Ad-GFP组指经携带GFP的腺病毒转导的ob/ob小鼠，Ad-ORM2组指经携带ORM2的腺病毒转导的ob/ob小鼠，每组n=4只小鼠。